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U TED- STATES PATENT OFFICE.

GEORG MERLIN G, OF BERLIN, GERMANY.

COMPOUND 0F GAMMA-OXYPlPERlDlN-CARBOACIDS AND PROCESS OF MAKING SAME.

SPEGIFIGATION forming part of Letters Patent No. 591,483, dated October 12, 1897.

Application filed September 13,1895- Serial No. 562,437. (Specimens) v To all whom it may concern.-

Be it known that I, GEoRe MERLING, a citizen of the German Empire, residing at 170 and 171 Muellerstrasse, Berlin, in the German Empire, have invented certain new and useful Improvements in Processes of Preparing- In this formula H signifies one atom of hydrogen, which can be replaced by an alkyl group, (alcoholic radicaL) and R signifies a stance: benzoyl, (0 11 00,) toluyl, (O H,CH

C0,) phenyl-acetyl, (C H OH OO,) phenylchloracetyl, (O H OHOlCO,) and cinnamyl, (O H CHOHOO.) All these compounds in the form of free bases are hardly soluble in water and form by the combination with inorganic and strong organic acids the corresponding salts. The hydriodates of these bases are hardly soluble and split up. by being perse veringly or continuously boiled with alkali, thereby forming, corresponding to the alkyl group and to the acidyl group and to gamma-oxypiperidin-carboacid of the said compounds, the corresponding alcohol, acid,and gainma-oxypiperidin-carboacid, respectively. I have also discovered that the gamma-oxypiperidin carboacids which possess a chemical constitution according to the above-mentioned formula, in which the acidyl group as well as the alkyl group bound to the carboxyl are replaced with hydrogen atoms, are obtained by combining hydrocyanic acid with triacetonamin or with bodies or combinations constituted analogous to the triacetonamin, such as with benzaldiacetonamin, vinyl-diacetonamin, &c., and then by saponifying the so-obtained cyanhydrins, (nitryls) The reactions that take place may be exmonovalent alkyl group, (alcoholic radical,) plained by the following equations:

H l I H H H cH \N/ CH oH CH Triacetonamin.

Nitryl of the tetramethylgamma-oxypiperidin-carboacid.

H @0011 110 ON O C. V *I H II II I O 0 /O C\ II I I A H +2II O: 11 I'M-NH OII C C OII CII C O CH cnf ou, 011 on,

l N H 'Ietramethyl-gamma-oxypipcridin-carboacid The preparation of the amma-oxypiperi- V din-carboacids will be understood from the /COOH following example of the preparation of C tetramethyl-gamma-oxypiperidin-carboacid: H H 5 To a concentrated aqueous solution ofone v v\ C/ kilogram of triacetonamin mixed with 0.5 kilogramofcyanidofpotassium,(ninety-eight OH I I H per cent.,) (which solution is to be cooled by C O means of ice,) 0.8 kilogram of concentrated 10 aqueous muriatic acid is added while stirring the mass. The solution is then saturated with gaseous hydrochloric acid,an d the'so- 1 formed cyanhydrin (nitryl) is thereupon saponified by boiling such solution'during se'V- Second. From vinyl-diacetonamin the tri- 15 eral hours in a reflux-condenser. The eX- methyl-gamma-oxypiperidin-carboacid havcess of hydrochloric acid is driven off on a ing a constitution according to the formula water-bath, the residue dissolved ind ilulted caustic-soda lye, and this solution is'acidu- HO COOH 6o lated at the boiling-temperature with acetic 7 2o acid. Nowtetramethyl-gamma-oxypiperidin U H carboacid separates as a colorless crystalline C powder, from which the adhering liquido'r solution is then eliminated as much as possi- OH I U ble in any suitable manner, as by suction or 2 by any known means, after which the crys- 7 5 talline powder is washed with water and CH3 H dried. The analogous gamma-oxypiperidincarboacids are obtained essentially in the same manner, of course substituting eq'uiva- 1 3o lent quantities of benzaldiacetonamin, 'vinyl- The n-alkyl-gamma-oxypiperidin-carbodiacetonamin, &c.,for the triaetonamin'macids can be obtained in the same way by ployed in the example abovedescribedl In starting with n-alkyltriacetonamin, or nthis way besides the tetramethyl-gammaalkyl benzaldiaeetonamin, &c.,the nsigoxypiperidin-carboacid, which melts at 285 nifying that' the alkyl group immediately 3 5 centigrade under decomposition, other gamafter the ether is bound directly to the nitroma-oxypiperidin-carboacids can be obtained, gen (N) atom. for instance: The properties of these gamma-oxypiperi- First. From benzaldiacetonamin the didin-carboacids are as follows: The gamma- 8o mcthylphcnyl gamma oxypiperidin carbooxypiperidin-carboacids form crystalline col- 4o acid, which melts at 250 to 270 centigrade, orless powders almost insoluble in water, in and having a constitution according to the alcohohin ether,in solutions of ammonia or of formula alkali-carbonates, and in dilute acetic acid.

In solutions of caustic alkalies and in diluted mineral acids said carboacids are readily soluble and can be precipitated in an unchanged state from alkaline solutions by means of acetic acid and from acid solutions by means of acetate of sodium, either slowly at low temperature or rapidly at a higher temperature, while they decompose when heated to a very high temperature, their color changing into black and develop gases. From these gamma-oxypiperidin-carboacids the new combinations or compounds, the composition of which has been explained in the beginning of this description, can be obtained according to the present invention by replacing the hydrogen of the carboxyl and of the imid group with alcoholic radicals and the hydrogen atom of the hydroxyl with acid radicals.

Production of ethers of the gamma-oxypiperidin-carboacids Example: Preparation of methylic ether of the tetramethyl-gamma-oxypiperidin-carboacid: Upon one kilogram, tetramethyl-gamma-oxypiperidin-carboacid an equal weight of methylic alcohol is poured. This liquid mass is heated to boiling and is saturated by introducing hydrochloric acid gas. After the mass has been allowed to stand for a day the greater part of the produced hydrochlorate of the methylic ether of the tetramethylgamma-oxypiperidin-carboacid is deposited in the form of colorless firm crystals, which, after being separated from the mother-lye, are washed withesmall quantities of methylic alcohol and then dried.

By the action of a solution of soda or of carbonate of soda the hydrochlorate is decomposed and the methylic ether of tetramethyl-gamma oxypiperidin-carboacid is set free. The same is constituted according to the formula 'Ho cooorn' \O/ r1 on on .N

and is a colorless, beautifully crystallizing body, the melting-point of which is from 69 to 70 centigrade.

In an analogous manner the methylic ethers of the dimethyl-phenyl-gam ma-oxypiperidincarboacid, or of trimethyl-gamma-oxypiperidin-carboacid, or of n-methyl-tetramethylgamma-oxypiperidin-carboacid are obtained, and in like manner also the preparation of other homologous ethers, for instance, of the ethylic ether of tetramethyl-gamma-oxypiperidin-carboacid,

. H H H II CH /OH on, on, N l H the melting-point of which is from 96 to 97 centigrade. All these ethers have the following properties: They are colorless crystalline bodies'which are soluble in almost all known solvents and are saponified either atonce by boiling with water or slowly in a cold aqueous solution, thereby separating the free gamma-oxypiperidin-carboaeid. By causing alkyl-iodid to act upon the free ethers the hydriodates of the n,- alkylated ethers may be obtained from which the free n-alkylated ethers are liberated by the addition of carbonate of sodium or of similar alkalies. The n-methyl-tetramethyl-gamma-oxypiperidin-carboacid-methyl-ether represents an oil which distils in the vacuum without undergoing decomposition. The n-methyl-trim ethylgamma-oxypiperidin-carboacid-methyl-ether crystallizes from ligroin into compact crystals, melting at 82 to 84 centigrade. Furthermore, compounds such as the ethers of the gamma-oxypiperidin-carboacids may be obtained having the composition expressed by the fundamental formula first herein referred to, in which compounds the hydrogen atom bound to the nitrogen atom has not been replaced by a radical.

Example: Preparation of methylic ether of benzoyl tetramethyl gamma oxypiperidincarboacid: Upon one kilogram pulverized dydrochlorate of the methylic ether of tetramethyl gamma oxypiperidin carboacid one kilogram benzoyl-chlorid is poured, and while stirring and under addition of a small quantity of zinc chlorid the mixture is heated on an oil-bath to from about 140 to 145 centigrade as long as hydrochloric acid develops. The brown syrup-like mass is then poured into ice-Water and repeatedly shaken with ether in order to eliminate excessive benzoylchlorid. By adding caustic-soda lye to the aqueous solution after being separated from the ether the methylic ether of benzoyl-tetra methyl r gamma oxypiperidin carboacid is precipitated in the form of a sticky gradually-hardening mass which is extracted by ether. When the ether is distilled oflf, the compound remains as a yellowish syrup, which on cooling changes into a crystalline mass and can be purified by dissolving in IIC soluble in cold water, and among these salts the formiate is the most soluble. It forms large bright crystals.

In an analogous manner the alkylic ethers of the characterized composition are prepared. Examples of the same may be mentioned, as follows:

Methylic ether of benzoyldimethylphenylgainma-oxypiperidin-carboacid c n ooo oooon,

crystallizes from ligroin in the form of colorless prisms, melting at 110 to 111 centigrade, and combines with inorganic and organic acids, thereby forming salts of neutral reaction. The hydrochlorate is easily soluble in water.

Methylie ether of benzoyltrimethyl-gammaoxypiperidin-carboacid c,n,coo 000011 0 II C C II ii I II OH. H

on on,

is a colorless crystallizing body, which melts at about 100 centigrade.

Of such salts the following have, for.

Ethylic ether of benzoyltetra-methyl-gainma-oxypiperidin-carboacid c n coo oooo n,

c n n /O C\ 1 1 a y I n on on, NB o( 3 forms colorless prisms, melting at to 86 centigrade.

Methylic ether of ortho-toluyltetra-methylga1nma-oxypiperidin-carboacid o,n,on,coo cooon,

n I n i l cn, en, CH3 CIT3 piperidin-earboaeids obtained as before described.

If the compounds to be prepared contain the same alkyl group instead of the hydrogen atom H of the earboxylic group as well as of the imid group, this method may be varied so as to treat a salt of the acidyl-gamma-oxypiperidin-carboaeid (obtainable by heating the corresponding gammaroxypiperidin-car boacid or its hydroehlorate with the chlorid of the aeidyl to be introduced into the said carboacid) or the free acid in an alcoholic solution with caustic alkali and halogen alkyl. In this Way the formation, for instance, of the methylic ether of n-methylbenzoyltetra- 1nethyl-gamma-oxypiperidin-carboacid takes place according to the following equation:

IIO

COOK

(3 11 000 C H OOO COOOH O O H O/ \O H H O/" \o H H H H H +KOH+2CH I: +2KI+H O OH OH CH C/H CH CH OH OH N f I H CH The production of the n-alkylated acidyl- C H COO OOOO H gamma oxypiperidin carboacid ethers can further be effected by acidulating a n-alkyl- O ated gamma-oxypiperidin-carboacid ora salt H H 5 thereof and then. etherifying the resulting C O compound-or by acidulating the ethers of the H H n-alkylated gamma oxypiperidin carboacid OH CH suitably with anhydrous acids. In this man- G O nor the following compounds can,for instance, OH CH 1 be obtained: N 60 Methylic ether of n-methylbenzoyltetra- 1nethyl-gamma-oxypiperidin-carboacid OH c ri ooo oooon O H H V v C O crystallizes in colorless prisms from ligroin, and melts at about 94 centigrade.

Ethylic ether of n-methylbenzoyltetra- 5o methyl-gamma-oXypiperidin-carboacid,

crystallizes in colorless compact crystals from ligroin and melts at about centigrade.

Ethylic ether of n-ethylbenzoyltetra- 65 methyl-gamma-oxypiperidin-carboacid,

OH oH I 2 5 crystallizes in colorless compactcrystals from so ligroin and melts at about 91 to 92 centigrade.

Methylic ether of n-propylbenzoyltetramethyl-gamma-oxypiperidin-carboacid,

crystallizes in needles, melting at about 95 centigrade. The hydrochlorate of this body crystallizes in needles and small leaves.

Methylic ether of n-methyl-cinnamyl-tetramethyl-gamma-oxypiperidin-carboacid,

o n ononooo ooocH,

l OH

melts at about 125 to 126 centigrade.

Having thus described my invention, what I claim as new therein, and desire to secure by Letters Patent, is-

r 1. As new chemical products, compounds of gamma-oxypiperidin-carboacids which are mostly colorless crystals containing acidyl as well as alkyl groups and whose composition corresponds to the formula ooorn H/ l l \H on H OHS N wherein H signifies a hydrogen atom which can be replaced by an alkyl group, R an compounds in the form of free bases being nearly insoluble in water, adapted to combine with inorganic and strong organic acids to form corresponding salts, the hydriodates being almost insoluble in water, while by continued boiling of said compounds with alkaacidyl group, and R an alkyl group, said lies the acidyl and alkyl groups are split off thereby forming the corresponding acid and alcohol and regenerating gamma-oxypiperidin-carboacid, substantially as set forth.

2. The process of manufacturing gammaoxypiperidin-carboacids containing acidyl as well as alkyl groups and whose composition corresponds to the formula R 0 COOR n I I H OH3\ whereby the acidyl and alkyl groups are introduced into combination with the gammaoxypiperidin-carboacid, substantially as set forth.

In testimony whereof I have signed my name, in the presence of two subscribing witnesses, this 31st day of August, 1895.

p I GEORG MERLING.

Witnesses:

W. HAUPT,

N. TOLMAN. 

